Studies on prostate-specific antigen and prostate cancer epidemiology

The prostate-specific antigen (PSA) is the main biomarker for diagnosis and treatment response monitoring in prostate cancer (PCa). In the first part of this thesis, we investigated the prognostic value of ultrasensitive PSAs (u-PSAs) in evaluating the risk of biochemical recurrence (BCR) and further progression after radical prostatectomy (RP). BCR after RP is defined by two consecutive PSA values greater or equal to 0.2 ng/ml. We found that u-PSA values above the threshold of 0.02-0.03 ng/ml predict progression to the BCR threshold (> 0.2 ng/ml). Furthermore, we demonstrated that the longitudinal modeling of u-PSA doubling time (uDT) could predict BCR after RP with very low PSA values. This can be beneficial in helping practitioners to avoid unnecessary adjuvant treatments or to start salvage treatments earlier for selected patients. In the second part of this thesis, PCa survival and mortality was investigated in the pre- and post-PSA eras. One of the cohort studies evaluated the impact of socioeconomic status (SES) on the survival of PCa patients in the pre- and post-PSA eras. Our study showed that men with localized PCa are otherwise healthier than the general male population, and the increased difference between relative and cancer-specific survival reflects the most likely selection of men for opportunistic PSA-testing. Men in higher SES groups had significantly lower risks of dying from PCa than those in the lower SES groups, which was probably due to more intensive diagnostic/treatment strategies and the increased intensity of health conscious men seeking medical services such as PSA testing.Prostataspesifinen antigeeni (PSA) on tärkein eturauhassyövän verinäytetutkimus. Tämän tutkimuksen ensimmäisessä vaiheessa selvitimme ultrasensitiivisen PSA:n (u-PSA) merkitystä eturauhassyövän seurannassa radikaalin eturauhasen poistoleikkauksen jälkeen. Biokemiallinen relapsi (BCR) leikkauksen jälkeen tarkoittaa kahta peräkkäistä PSA-arvoa, jotka ylittävät arvon 0.2 ng/ml. Tutkimuksessamme osoitimme, että jos u-PSA nousee tasolle 0.02-0.03 ng/ml, PSA-pitoisuus nousee yli 90% potilaista myös BCR-tasolle. Lisäksi osoitimme, että u-PSA:n kahdentumisajan (uDT) longitudinaalinen mallintaminen auttaa BCR:n ennustamisessa jo hyvin pienillä u-PSA-arvoilla. Tämä on erityisen hyödyllistä, kun halutaan välttää turhia liitännäishoitoja ja toisaalta kohdentaa ne riittävän ajoissa oikeille potilaille. Tutkimuksen toisessa vaiheessa eturauhassyöpäkuolleisuutta ja potilaiden elossaoloa (survival) tutkittiin ennen ja jälkeen PSA-testauksen yleistymistä. Tutkimus toteutettiin rekisteritutkimuksena Suomen Syöpärekisterin ja Tilastokeskuksen tiedoista. Tilastokeskuksen tiedoista selvitettiin vuosittainen eturauhassyöpäpotilaiden ikäryhmittäinen kuolleisuus suhteessa vertailuväestön kuolleisuuteen. Samoin potilaiden sosioekonomisen asema (SES) selvitettiin Tilastokeskuksesta. Tutkimus osoitti, että miehet joilla todettiin paikallinen eturauhassyöpä olivat muuten terveempiä kuin vertailuväestö. Eritoten PSA-testin käyttöönoton jälkeen eturauhassyöpäpotilaiden suhteellinen elossaololuku oli selvästi korkeampi kuin syöpäspesifinen elossaololuku potilailla, joilla oli paikallinen eturauhassyöpä. Tämä viittaa siihen, että nämä miehet valikoituivat useammin opportunistiseen PSA-seulontaan. Tutkimus osoitti myös, että korkeampi SES korreloi huomattavasti pienempään syöpäspesifinen kuolleisuuteen. Tämä on oletettavasti selitettävissä, sillä että näille miehille tehtiin enemmän eturauhassyöpädiagnostiikkaa ja heitä hoidettiin intensiivisemmin kuin alhaisemmassa SES-asemassa olevia. Näille miehille myös ilmeisimmin tehtiin enemmän PSA-testausta. Yhteenvetona voidaan todeta, että u-PSA voi olla hyödyllinen taudin uusimisen arvioinnissa leikkauksen jälkeen, ja että PSA-testin käyttö pitäisi optimoida kaikille väestöryhmille, välttäen yli- ja alidiagnostiikkaa

Survival and mortality of elderly men with localized prostate cancer managed with primary androgen deprivation therapy or by primary observation

Background Androgen deprivation therapy (ADT) remains a primary treatment for localized prostate cancer (PCa) even though there is no evidence that its use is beneficial in the absence of curative treatment. Methods Men aged >= 70 years (n = 16,534) diagnosed with localized PCa from 1985 to 2014 and managed either with primary observation or ADT in the absence of curative treatment were included. The cases were identified from the population-based Finnish Cancer Registry. We estimated the standardized mortality ratios (SMR) for overall mortality by treatment group. We determined the relative risk (RR) of PCa-specific mortality (PCSM) and other-cause mortality between the two treatment groups. Survival was determined using the life table method. Two age groups (70-79 years and >= 80 years) and three calendar time cohorts (1985-1994, 1995-2004, and 2005-2014) were compared following adjustment of propensity score matching between the treatment groups with four covariates (age, year of diagnosis, educational level, and hospital district). Follow-up continued until death or until December 31, 2015. Results Patients in the observation group had lower overall SMRs than those in the ADT group in both age cohorts over the entire study period. PCSM was higher in men aged 70-79 years undergoing primary ADT compared to those managed by observation only (RR: 1.70, 95% confidence interval [CI]: 1.29-2.23 [1985-1994]; RR 1.55, 95% CI: 1.35-1.84 [1995-2004]; and RR 2.71, 95% CI: 2.08-3.53 [2005-2014]); p = 0.005 for periodic trend. A similar trend over time was also observed in men aged > 80 years; (p for age-period interaction = 0.237). Overall survival was also higher among men in their 70's managed by observation compared to those undergoing ADT. Conclusions Primary ADT within four months period from diagnosis is not associated with improved long-term overall survival or decreased PCSM compared to primary conservative management for men with localized PCa. However, this observational study's conclusions should be weighted with confounding factors related to cancer aggressiveness and comorbidities.Peer reviewe

Survival and mortality of elderly men with localized prostate cancer managed with primary androgen deprivation therapy or by primary observation

Background Androgen deprivation therapy (ADT) remains a primary treatment for localized prostate cancer (PCa) even though there is no evidence that its use is beneficial in the absence of curative treatment. Methods Men aged >= 70 years (n = 16,534) diagnosed with localized PCa from 1985 to 2014 and managed either with primary observation or ADT in the absence of curative treatment were included. The cases were identified from the population-based Finnish Cancer Registry. We estimated the standardized mortality ratios (SMR) for overall mortality by treatment group. We determined the relative risk (RR) of PCa-specific mortality (PCSM) and other-cause mortality between the two treatment groups. Survival was determined using the life table method. Two age groups (70-79 years and >= 80 years) and three calendar time cohorts (1985-1994, 1995-2004, and 2005-2014) were compared following adjustment of propensity score matching between the treatment groups with four covariates (age, year of diagnosis, educational level, and hospital district). Follow-up continued until death or until December 31, 2015. Results Patients in the observation group had lower overall SMRs than those in the ADT group in both age cohorts over the entire study period. PCSM was higher in men aged 70-79 years undergoing primary ADT compared to those managed by observation only (RR: 1.70, 95% confidence interval [CI]: 1.29-2.23 [1985-1994]; RR 1.55, 95% CI: 1.35-1.84 [1995-2004]; and RR 2.71, 95% CI: 2.08-3.53 [2005-2014]); p = 0.005 for periodic trend. A similar trend over time was also observed in men aged > 80 years; (p for age-period interaction = 0.237). Overall survival was also higher among men in their 70's managed by observation compared to those undergoing ADT. Conclusions Primary ADT within four months period from diagnosis is not associated with improved long-term overall survival or decreased PCSM compared to primary conservative management for men with localized PCa. However, this observational study's conclusions should be weighted with confounding factors related to cancer aggressiveness and comorbidities.Peer reviewe

Differential Predictive Roles of A- and B-Type Nuclear Lamins in Prostate Cancer Progression

Background Prostate cancer (PCa) is the most common cancer among men in western countries. While active surveillance is increasingly utilized, the majority of patients are currently treated with radical prostatectomy. In order to avoid over-treatment, there is an indisputable need for reliable biomarkers to identify the potentially aggressive and lethal cases. Nuclear intermediate filament proteins called lamins play a role in chromatin organization, gene expression and cell stiffness. The expression of lamin A is associated with poor outcome in colorectal cancer but to date the prognostic value of the lamins has not been tested in other solid tumors. Methods We studied the expression of different lamins with immunohistochemistry in a tissue microarray material of 501 PCa patients undergoing radical prostatectomy and lymph node dissection. Patients were divided into two staining categories (low and high expression). The correlation of lamin expression with clinicopathological variables was tested and the association of lamin status with biochemical recurrence (BCR) and disease specific survival (DSS) was further analyzed. Results Low expression of lamin A associated with lymph node positivity (p Conclusions These results suggest differential roles for lamins in PCa progression. Reduced amounts of lamin A/C and B2 increase risk for lymph node metastasis and disease specific death possibly through increased nuclear deformability while high expression of lamin B1 predicts disease recurrence.Peer reviewe

IMAGINE—IMpact Assessment of Guidelines Implementation and Education : The Next Frontier for Harmonising Urological Practice Across Europe by Improving Adherence to Guidelines

Publisher Copyright: © 2020 European Association of UrologyAdherence to national and international clinical practice guidelines is suboptimal throughout Europe. The European Association of Urology Guidelines Office project “IMAGINE” (IMpact Assessment of Guidelines Implementation and Education) has been developed to measure baseline adherence to urological guideline recommendations across Europe and to identify issues that drive nonadherence.Non peer reviewe

New prostate cancer grade grouping system predicts survival after radical prostatectomy

Histological Gleason grading of prostate cancer has been through modifications and conjoined into a Grade Grouping system recently. The aim of this study was to determine whether the new Grade Grouping system predicts disease-specific and all-cause mortality after radical prostatectomy. We constructed a clinical database consisting of all consecutively radical prostatectomy treated men between 1983 and 1998 and between 2000 and 2005 at the Helsinki University Hospital and at the Turku University Hospital, respectively. Patients' all-cause and prostate cancer specific mortality information was updated in November 2015 from the Finnish Cancer Registry. Secondary therapy information was also available from the patients' records at Helsinki. Univariate and multivariate statistical analyses were performed to assess predictive significance of the Grade Grouping system. Grade Grouping associated independently with increased risk of prostate cancer specific mortality within 15 years of follow-up in a multivariable model containing age at operation, diagnostic prostate-specific antigen, pathological stage and lymph node status at operation. Additionally, the all-cause mortality-free survival time and time to secondary therapies were different between the Grade Groups, emphasized in the subanalysis of Grade Groups 1-2 versus Grade Groups 3-5. We can conclude that the new Grade Grouping system is feasible in predicting prostate cancer specific survival after radical surgical treatment. Grade Grouping offers a simpler way to interpret the predicted course of the disease to individual patients and thus may help in justifying more conservative follow-up approaches, especially in the lower Grade Group patients. (C) 2018 The Authors. Published by Elsevier Inc.Peer reviewe

Longitudinal modeling of ultrasensitive and traditional prostate-specific antigen and prediction of biochemical recurrence after radical prostatectomy

Ultrasensitive prostate-specific antigen (u-PSA) remains controversial for follow-up after radical prostatectomy (RP). The aim of this study was to model PSA doubling times (PSADT) for predicting biochemical recurrence (BCR) and to capture possible discrepancies between u-PSA and traditional PSA (t-PSA) by utilizing advanced statistical modeling. 555 RP patients without neoadjuvant/adjuvant androgen deprivation from the Turku University Hospital were included in the study. BCR was defined as two consecutive PSA values > 0.2 ng/mL and the PSA measurements were log(2)-transformed. One third of the data was reserved for independent validation. Models were first fitted to the post-surgery PSA measurements using cross-validation. Major trends were then captured using linear mixed-effect models and a predictive generalized linear model effectively identified early trends connected to BCR. The model generalized for BCR prediction to the validation set with ROC-AUC of 83.6% and 95.1% for the 1 and 3 year follow-up censoring, respectively. A web-based tool was developed to facilitate its use. Longitudinal trends of u-PSA did not display major discrepancies from those of t-PSA. The results support that u-PSA provides useful information for predicting BCR after RP. This can be beneficial to avoid unnecessary adjuvant treatments or to start them earlier for selected patients.Peer reviewe

Intraoperative complications in kidney tumor surgery : critical grading for the European Association of Urology intraoperative adverse incident classification

Introduction The European Association of Urology committee in 2020 suggested a new classification, intraoperative adverse incident classification (EAUiaiC), to grade intraoperative adverse events (IAE) in urology. Aims We applied and validated EAUiaiC, for kidney tumor surgery. Patients and methods A retrospective multicenter study was conducted based on chart review. The study group comprised 749 radical nephrectomies (RN) and 531 partial nephrectomies (PN) performed in 12 hospitals in Finland during 2016-2017. All IAEs were centrally graded for EAUiaiC. The classification was adapted to kidney tumor surgery by the inclusion of global bleeding as a transfusion of >= 3 units of blood (Grade 2) or as >= 5 units (Grade 3), and also by the exclusion of preemptive conversions. Results A total of 110 IAEs were recorded in 13.8% of patients undergoing RN, and 40 IAEs in 6.4% of patients with PN. Overall, bleeding injuries in major vessels, unspecified origin and parenchymal organs accounted for 29.3, 24.0, and 16.0% of all IEAs, respectively. Bowel (n = 10) and ureter (n = 3) injuries were rare. There was no intraoperative mortality. IAEs were associated with increased tumor size, tumor extent, age, comorbidity scores, surgical approach and indication, postoperative Clavien-Dindo (CD) complications and longer stay in hospital. 48% of conversions were reactive with more CD-complications after reactive than preemptive conversion (43 vs. 25%). Conclusions The associations between IAEs and preoperative variables and postoperative outcome indicate good construct validity for EAUiaiC. Bleeding is the most important IAE in kidney tumor surgery and the inclusion of transfusions could provide increased objectivity.Peer reviewe

Increased Expression and Altered Cellular Localization of Fibroblast Growth Factor Receptor-Like 1 (FGFRL1) Are Associated with Prostate Cancer Progression

Fibroblast growth factor receptors (FGFRs) 1–4 are involved in prostate cancer (PCa) regulation, but the role of FGFR-like 1 (FGFRL1) in PCa is unclear. FGFRL1 expression was studied by qRT-PCR and immunohistochemistry of patient tissue microarrays (TMAs) and correlated with clinical patient data. The effects of FGFRL1 knockdown (KD) in PC3M were studied in in vitro culture models and in mouse xenograft tumors. Our results showed that FGFRL1 was significantly upregulated in PCa. The level of membranous FGFRL1 was negatively associated with high Gleason scores (GSs) and Ki67, while increased cytoplasmic and nuclear FGFRL1 showed a positive correlation. Cox regression analysis indicated that nuclear FGFRL1 was an independent prognostic marker for biochemical recurrence after radical prostatectomy. Functional studies indicated that FGFRL1-KD in PC3M cells increases FGFR signaling, whereas FGFRL1 overexpression attenuates it, supporting decoy receptor actions of membrane-localized FGFRL1. In accordance with clinical data, FGFRL1-KD markedly suppressed PC3M xenograft growth. Transcriptomics of FGFRL1-KD cells and xenografts revealed major changes in genes regulating differentiation, ECM turnover, and tumor–stromal interactions associated with decreased growth in FGFRL1-KD xenografts. Our results suggest that FGFRL1 upregulation and altered cellular compartmentalization contribute to PCa progression. The nuclear FGFRL1 could serve as a prognostic marker for PCa patients